ZLN-024

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型 AMPK 变构激活剂，对线粒体功能或 ADP/ATP 比率没有影响；直接激活重组 AMPK α1β1γ1 及其同源物 α2β1γ1，EC50 分别为 0.42 uM 和 0.95 uM。

A novel AMPK allosteric activator that has no effect on mitochondrial function or the ADP/ATP ratio; directly activate recombinant AMPK α1β1γ1 and its homologue α2β1γ1 with EC50 of 0.42 uM and 0.95 uM, respectively; also directly activate recombinant AMPK α1β2γ1 (EC50=1.1 μuM) and AMPK α2β2γ1 (EC50=0.13 uM); activates AMPK in L6 myotubes and stimulates glucose uptake and fatty acid oxidation; improves glucose tolerance, liver tissue weight, triacylglycerol and decreases the total cholesterol content in db/db mice (15 mg/kg/day).Diabetes Preclinical.

ZLN024 allosterically stimulates active AMPK heterotrimers and the inactive α1 subunit truncations α1 (1-394) and α1 (1-335) but not α1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Cα. ZLN024 activates AMPK in L6 myotubes and stimulates glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. Using the established scintillation proximity assay (SPA) assay, random screening against the AMPK α1β1γ1 heterotrimer is performed and a new AMPK activator, ZLN024 is found. ZLN024 directly activates recombinant AMPK α1β1γ1 and its homologue α2β1γ1 in a concentration-dependent manner. ZLN024 increases the activity of α1β1γ1 by 1.5-fold and has an EC50 of 0.42 μM, and it increases the activity of α2β1γ1 by 1.7-fold with an EC50 of 0.95 μM. ZLN024 also directly activates recombinant AMPK α1β2γ1, by 1.7-fold with an EC50 of 1.1 μM; and AMPK α2β2γ1, by 1.6-fold with an EC50 of 0.13 μM.

C57BKS db/db mice are administered a 15 mg/kg/day dose of ZLN024 by daily gavage for 5 weeks; 250 mg/kg/day Metformin (Met) is used as a positive control. During the treatment period, there is no significant alteration in food intake and body weight compared with the vehicle group. After 4 weeks of treatment, ZLN024 improves glucose tolerance. ZLN024 reduces the fasting blood glucose by 15%. Liver tissue weight, triacylglycerol and the total cholesterol content are decreased.

ZLN024

Membrane Transporter/Ion Channel

AMPK

AMPK

Metabolic Disease

Diabetes

723249-01-2

325.2241

C13H13BrN2OS

>98% (HPLC)

10 mM in DMSO

CC1=CC(=C(C=C1)OCCSC2=NC=CC=N2)Br

Pyrimidine, 2-[[2-(2-bromo-4-methylphenoxy)ethyl]thio]-

(-20℃)

With Ice Pack

≥ 2 years